Histone lysine specific demethylase 1 (LSD1) has been recognized as an important modulator in post-translational process in epigenetics.Dysregulation of LSD1 has been implicated in the development of various cancers.Herein, we report the discovery 100w products of the hit compound 8a (IC50 = 3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15u (IC50 = 49 nmol/L, and Ki = 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3K4me2, and was selective to LSD1 over MAO-A/B.
Docking studies were performed to rationalize the potency of compound 15u.Compound 15u also showed strong antiproliferative activity against four leukemia cell lines (OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC50 values of 1.79, 1.30, 0.
45, 1.22 and 1.40 μmol/L, respectively.In THP-1 cell line, 15u significantly inhibited colony formation and caused remarkable morphological changes.
Compound 15u induced expression of CD86 and CD11b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation.The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazole-fused pyrimidine derivatives are click here new scaffolds for the development of LSD1/KDM1A inhibitors.KEY WORDS: Epigenetic regulation, Histone demethylase, LSD1, Pyrimidine-triazole, Mercapto heterocycles, Antiproliferative ability, AML treatment, Structure–activity relationships (SARs).